This is a revised application for Project by Caligiuri. The proposed Project will test specific hypotheses in regard to the effects of METH and HIV, singly and in combination, on neuromotor function. The Project will also explore the possible added effects of HCV. Methamphetamine (METH) exerts powerful influences on brain systems regulating sensorimotor functions. Movement disorders associated with chronic METH use may stem from a neurotoxic mechanism involving reduction in dopamine and/or a disinhibition mechanism related to reduction in enkephalin/GABA mediated inhibition. If the neurotoxicity mechanism is correct, we would hypothesize that the movement disorder would take the form of parkinsonism and would persist through periods of abstinence. However, if basal ganglia pathways mediating response inhibition are involved, the movement disorder would manifest as motor disinhibition. These effects of METH need to be understood in the context of risk that METH abusers face of infection by HIV and HCV. The former is known to cause brain disease, and recent evidence also suggests HCV may infect the brain. We plan to utilize quantitative instrumental measures of parkinsonism and motor disinhibition. The within-project aims are to: (1) systematically delineate the specific types of motor disturbances associated with HIV and METH abuse; (2) evaluate whether longer periods of abstinence from METH use are associated with improvement in the severity of neuromotor disturbance among chronic METH abusers, and examine moderators of this process (e.g., HCV); and (3) clarify potential interactions between the neuromotor and neurocognitive disturbances associated with METH abuse and HIV by assessing whether subjects who are cognitively impaired also exhibit neuromotor disturbances. This Project will function synergistically with each of the other Projects by linking the patterns of movement disorders that are thought to reflect specific neural circuitries to the anatomic, mechanistic, and cognitive information from other Projects.